Project Summary Colorectal cancer (CRC) is the second leading cause of cancer-related deaths in the US. Over half of CRC patients have regional or distant metastasis at the time of diagnosis, and those with metastases to other organs have a 5-year survival rate of only ~12%. Checkpoint blockade immunotherapy stimulates the host immune system to generate an antitumor immune response, and has showed impressive results treating patients with mismatch repair (MMR) deficient CRC. However, up to 95% of patients with metastatic CRC (mCRC) have MMR- proficient, microsatellite-stable disease, who do not benefit from current immunotherapy. We propose to develop nanoscale coordination polymer-based targeted nanomedicines containing oxaliplatin and dihydroartemesinin (DHA), two immunogenic chemotherapeutics, for treating mCRC. EGFR-targeted nanomedicines can exert direct cytotoxic effects on CRC cells, and simultaneously induce and potentiate an antitumor immune effect. We propose the following Specific Aims in order to develop a novel combined chemotherapeutic nanomedicine and checkpoint blockade immunotherapy for the effective treatment of mCRC. Aim 1: Evaluate the mechanisms of OxPt/DHA nanoparticle anticancer efficacy on CRC cells. Aim 2: Actively target OxPt/DHA nanoparticles to CRC with an anti-EGFR Fab. Aim 3: Evaluate the anticancer efficacy of OxPt/DHA and EGFR-OxPt/DHA nanoparticles in orthotopic mouse models of CRC. Aim 4: Elucidate the immune mechanisms of antitumor response in mice treated with OxPt/DHA or EGFR-OxPt/DHA nanoparticles in combination with PD-L1 antibody. Through these aims, we seek to establish a new paradigm for the treatment of mCRC by increasing the response rate and therapeutic efficacy of immunotherapy for mCRC. Given that checkpoint blockade immunotherapies have been approved by FDA to treat multiple types of cancers, our strategy of utilizing chemotherapeutic nanomedicine as an immune system booster to potentiate checkpoint blockade can have broad impact on treating other metastatic cancers.